Hypercholesterolemia is known to be one of the prime etiological components of cardiovascular disease such as atherosclerosis, and there is still no effective antihypercholesterolemic agent available that has found wide patient acceptance. The bile acid sequestrants seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time and they are not very palatable.
There are agents known, however, that are very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. These agents include the natural fermentation products compactin and mevinolin and a variety of semi-synthetic and totally synthetic analogs thereof. These compounds have the following general structural formula: ##STR2## wherein R is ##STR3##
One group of totally synthetic analogs are disclosed in U.S. Pat. No. 4,375,475 and have the same general structural formula: ##STR4## wherein R is ##STR5## In the usual course of synthesis of these lactones an intermediate ester and dihydroxy acid are encountered: ##STR6## Each of these entities, as well as the lactone, demonstrate antihypercholesterolemic activity in vivo, of comparable magnitude. However, for these compounds to manifest a useful degree of activity, it is essential that the compounds have the particular 3R:5S/3S:5R steric relationship shown in the structures.
One of the prior art synthesis of these compounds comprises reduction of .beta.-hydroxyketones 2a or 2b ##STR7## A stereoselective process for the reduction of .beta.-hydroxyketones 2a and 2b have been described and disclosed in a copending U.S. patent application, Ser. No. 725,891, filed Apr. 25, 1985.